Personalised Warfarin Therapy

Remember that all models are wrong; the practical question is how wrong do they have to be to not be useful

— George E P Box, Professor of Statistics, University of Wisconsin (1919-2013)

Pharmacometric models, which are based on mathematical and statistical models, can provide an improved understanding of the dose-response relationship, and help identify and quantify factors that influences variability in drug response. With a better understanding of the dose-effect relationship, therapy can be truly individualised. In the work presented here, pharmacometric models have been developed to describe the relationship between warfarin dose and anticoagulant effect over time for both adults and children. This type of models have the potential to provide individualised start doses, but more importantly, improve dose adjustment practices and provide more efficient individualisation of warfarin by integrating modelling and simulation into clinical decision support systems.

Warfarin is the most widely prescribed anticoagulant for prevention and treatment of thromboembolic events. Although highly effective, the use of warfarin is limited by a narrow therapeutic range combined with a large difference in the dose required for adequate anticoagulation. To achieve a favourable balance between the wanted antithrombotic effect and the risk of bleeding, it is important to identify the right dose for individual patients. The challenge is to know beforehand what the right dose should be, but also how to adjust the dose once treatment has started to achieve and maintain the desired therapeutic effect, and at the same time minimise the risk of adverse bleeding events. There is a certain degree of understanding of the effect of clinical, demographic and genetic factors on the variability in warfarin maintenance dose in adults, but not how these factors influences dose requirements in children or how they influences the response to warfarin over time. Examples of temporal outcomes of interest in warfarin therapy include the time delay between dose administration and INR response, extent and rate of drug accumulation, and time to stable treatment response.